The goal of this application is to develop tumor necrosis factor (TNF)-inhibiting compounds as neuroprotectant drugs for treating Alzheimer's disease (AD). Current FDA-approved AD interventions are symptomatic treatments with limited efficacy which do not affect AD etiology or modify the course of disease progression. Thus, a critical need exists for a novel AD treatment directed towards AD pathophysiology. Recent studies implicate the neuroinflammatory cytokine TNF- as a key mediator in AD-associated neurodegenerative pathology. Multiple preclinical and clinical studies indicate that TNF is a druggable molecular target to modify the course of AD progression. Preliminary Studies demonstrate that our lead compound, IDT, shows potent TNF inhibition in vitro. Preliminary Studies also demosntrate that 100 mg/kg IDT administered orally every day for two months significantly improved working memory in the triple-transgenic (3xTg) AD mouse model. IDT also modulated brain TNF protein levels after daily treatment for two months in AD mice. No morbidity, mortality or any obvious side effects were observed despite the long-term daily treatment regiment with IDT. Taken together, these data strongly suggest that our lead compound is an excellent anti-AD drug candidate. The proposed preclinical study is designed to evaluate the oral efficacy of IDT in 9-month old 3xTg AD mice which mimic moderate symptoms and pathology. Aim 1: Determine the effect of oral administration of IDT mixed in diet on cognitive performance in 3xTg AD mice. Aim 2: Determine the effect of the IDT on TNF- levels, Ass1-40/Ass1-42 levels, microglial activation, synaptophysin and degenerating neurons in 3xTg AD mice. PUBLIC HEALTH RELEVANCE: Alzheimer's Disease (AD) is a significant neurological problem affecting 4.5 million of our senior U.S. citizens. The present research aims to develop an effective drug that can be taken orally to target the underlying neuroinflammation in AD to modify disease progression and improve cognitive function.